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TERTc.875C>TUncertain significance
Print report
Variant interpretation report

TERT c.875C>T, p.(Thr292Met)

NM_198253.2:c.875C>T NP_937983.2:p.(Thr292Met) View identifiers
Classification
Uncertain significance

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

About TERT

No gene-level summary was recorded for this case.

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.
01The reasoning

How it was classified

The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 1 Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting

This variant is absent from gnomAD v2.1 and gnomAD-Canada v1.0, and is present at an extremely low frequency in gnomAD v4.1 (AF=6.3e-7, 1/1,586,736 alleles, 0 homozygotes). The highest subpopulation frequency is in South Asian (AF=1.14e-5). These frequencies are well below the 0.1% threshold for PM2 in genes associated with rare disease.

Benign criteria applied · 1
BP4Supporting
BP4 · supporting

Multiple lines of computational evidence suggest this variant is tolerated and does not impact gene product function. BayesDel predicts a benign score (-0.237), REVEL score is low (0.296, below the 0.5 threshold for deleterious prediction), and SpliceAI predicts no splicing impact (max delta = 0.01). The convergence of independent computational tools toward a benign prediction satisfies BP4 at supporting level.

Recorded classification: Uncertain significance

gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, BP4 supporting; combination = 1 supporting + 1 supporting benign, which maps to VUS.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

SpliceAI score
0.010 maximum delta

Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP4 → SpliceAI ↗
ClinVar submissions
2 reported laboratory submissions

2 Uncertain significance. ClinVar API review status: criteria provided, multiple submitters, no conflicts.

Context only ClinVar ↗
Functional evidence
Statement recorded

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. TERT is an enzyme that functions to maintain telomere length and genomic stability. The TERT promoter is frequently mutated in various cancer types.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
2 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV99716364, n = 2 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

26 criteria with recorded statuses: 2 met · 21 not met · 0 not assessed · 3 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP4BP5BP6BP7
Met Not met Not assessed Not applicable

NM_198253.2:c.875C>T (p.Thr292Met) is a missense variant in exon 2 of TERT. TERT is associated with autosomal dominant and recessive telomere biology disorders including dyskeratosis congenita, bone marrow failure, and pulmonary fibrosis.

This variant is extremely rare in population databases, absent from gnomAD v2.1 and gnomAD-Canada, and present at an allele frequency of 6.3e-7 (1/1,586,736 alleles, 0 homozygotes) in gnomAD v4.1, satisfying PM2 at supporting strength.

Multiple lines of computational evidence suggest this variant is tolerated: BayesDel score is -0.237 (benign range), REVEL score is 0.296 (below the 0.5 pathogenicity threshold), and SpliceAI predicts no splicing impact (max delta = 0.01), collectively satisfying BP4 at supporting strength.

No functional studies, case-control data, segregation analysis, or de novo observations were identified for this variant. ClinVar reports two clinical laboratory submissions, both classifying the variant as Uncertain significance. All reviewed publications discuss TERT at the gene level and do not mention this specific variant.

Under the generic ACMG/AMP 2015 classification framework, the variant NM_198253.2:c.875C>T (p.Thr292Met) is classified as a Variant of Uncertain Significance (VUS), with balanced pathogenic (PM2_supporting) and benign (BP4_supporting) evidence. Additional evidence such as functional characterization, segregation data, or case-control studies would be needed to reclassify this variant.

Met · 2

PM2 SupportingThis variant is absent from gnomAD v2.1 and gnomAD-Canada v1.0, and is present at an extremely low frequency in gnomAD v4.1 (AF=6.3e-7, 1/1,586,736 alleles, 0 homozygotes). The highest subpopulation frequency is in South Asian (AF=1.14e-5). These frequencies are well below the 0.1% threshold for PM2 in genes associated with rare disease. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1.
  • gnomAD v4.1: AF=6.3e-7
  • 1/1
  • 586
  • 736 alleles
  • 0 homozygotes.
  • Absent from gnomAD-Canada v1.0.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BP4 SupportingMultiple lines of computational evidence suggest this variant is tolerated and does not impact gene product function. BayesDel predicts a benign score (-0.237), REVEL score is low (0.296, below the 0.5 threshold for deleterious prediction), and SpliceAI predicts no splicing impact (max delta = 0.01). The convergence of independent computational tools toward a benign prediction satisfies BP4 at supporting level. Details ▾Hide ▴
Evidence considered
  • BayesDel: -0.237 (benign prediction).
  • REVEL: 0.296 (below 0.5 threshold).
  • SpliceAI: max delta 0.01 (no predicted splice impact).
Sources
bayesdelrevelspliceai ↗

Not met · 21 · evaluated, threshold not reached

PS1 No evidence of a different nucleotide change at the same position (c.875) resulting in the same amino acid change (p.Thr292Met) that has been classified as pathogenic. PS1 requires an alternate substitution at the same nucleotide position producing the same protein change with established pathogenicity. Details ▾Hide ▴
Evidence considered
  • No alternate nucleotide change at c.875 producing p.Thr292Met identified in ClinVar or literature.
PS2 No de novo occurrence data are available for this variant. PS2 requires confirmed de novo observation in a patient with the disease and no family history. Details ▾Hide ▴
Evidence considered
  • No de novo data identified in ClinVar submissions or literature.
Still missing
  • No parental testing data available.
PS3 No variant-specific functional studies have been identified for NM_198253.2:c.875C>T. OncoKB reports unknown oncogenic effect with no variant-specific reviewed functional evidence. COSMIC reports two somatic occurrences (COSV99716364), but somatic counts alone do not constitute functional evidence. No systematic range characterization (tiling screen, saturation mutagenesis, or truncation series) includes this residue. Reviewed ClinVar-associated and PVS1 gene-context publications confirmed none contain functional data for this variant. Details ▾Hide ▴
Evidence considered
  • OncoKB classification: Unknown Oncogenic Effect. COSMIC: 2 somatic occurrences
  • no functional characterization.
Still missing
  • No experimental functional data for this variant or a systematically characterized range including p.Thr292.
Sources
oncokb ↗
PS4 No significant enrichment of this variant in affected individuals compared to controls has been demonstrated. The variant is present at extremely low frequency in gnomAD v4.1 (1/1,586,736 alleles; AF=6.3e-7). Two clinical laboratories have reported this variant in ClinVar as VUS, but these submissions do not provide case counts or case-control evidence. The ClinVar-associated publications are GeneReviews and PDQ summaries that discuss TERT-related disorders at the gene level without mentioning this variant. Details ▾Hide ▴
Evidence considered
  • Extremely rare in population (1 allele in 1
  • 586
  • 736). ClinVar VUS from 2 clinical labs
  • no case-control data.
Still missing
  • No case counts or case-control studies available.
Sources
clinvar ↗gnomad_v4 ↗
PM1 The variant affects codon 292, which lies within the TEN (telomerase essential N-terminal) domain of TERT. However, this residue is not within a statistically significant mutational hotspot as determined by cancerhotspots.org, and no residue-specific functional or clinical evidence establishes this position as a critical residue. The TEN domain is a large functional domain, and PM1 at domain level typically requires a mutational hotspot or well-established critical functional sub-region. This missense variant does not remove or structurally disrupt the domain. Details ▾Hide ▴
Evidence considered
  • Position 292 in TEN domain
  • but not a statistically significant hotspot per cancerhotspots.org. No residue-specific functional evidence.
Still missing
  • No residue-specific evidence for p.Thr292 as a critical functional residue.
Sources
oncokb ↗
PM6 No de novo data are available for this variant. PM6 requires a confirmed de novo observation with maternity and paternity confirmed. Neither of the two ClinVar submissions (Labcorp/Invitae, Ambry Genetics) reports de novo status. Details ▾Hide ▴
Evidence considered
  • No de novo data in ClinVar submissions or literature.
Still missing
  • No parental testing data available.
Sources
clinvar ↗
PP1 No segregation data are available for this variant. PP1 requires cosegregation of the variant with disease in multiple affected family members. Details ▾Hide ▴
Evidence considered
  • No segregation data identified.
Still missing
  • No family studies or segregation analysis available.
PP2 No gene-specific missense constraint data (HCI prior) are available for TERT. PP2 requires demonstration that the gene has a low rate of benign missense variation (high missense Z-score) and that missense variants are a common mechanism of disease. TERT is known to harbor both pathogenic missense and truncating variants, but without explicit constraint metrics, PP2 cannot be applied. Details ▾Hide ▴
Evidence considered
  • HCI prior not available for TERT. No explicit missense constraint metrics in evidence packet.
Still missing
  • Missense constraint data (Z-score) not available
  • could be assessed with additional database lookup.
PP3 Multiple in silico tools do not support a damaging effect for this variant. REVEL score is 0.296 (below the commonly used 0.5 threshold for pathogenicity). BayesDel score is -0.237 (in the benign range). SpliceAI predicts no splicing impact (max delta = 0.01). These computational predictions do not meet the threshold for PP3, which requires multiple lines of computational evidence supporting a deleterious effect. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.296 (below 0.5 pathogenicity threshold).
  • BayesDel: -0.237 (benign prediction).
  • SpliceAI: max delta 0.01 (no splice impact).
Sources
revelbayesdelspliceai ↗
PP4 No patient phenotype data are available to evaluate whether the clinical presentation is specific for TERT-related disease (telomere biology disorders including dyskeratosis congenita, bone marrow failure, pulmonary fibrosis). PP4 requires the patient's phenotype or family history to be highly specific for the gene/disease. Details ▾Hide ▴
Evidence considered
  • No patient phenotype data available in the evidence packet.
Still missing
  • Patient phenotype information not provided.
PP5 This variant has been reported in ClinVar as Uncertain significance by two clinical laboratories (Labcorp/Invitae and Ambry Genetics). Neither has classified the variant as pathogenic or likely pathogenic. The ClinVar-associated publications (GeneReviews, PDQ summaries) are gene-level reviews and do not specifically assess or classify this variant. PP5 requires a reputable source to have classified the variant as pathogenic. Details ▾Hide ▴
Evidence considered
  • ClinVar: VUS from 2 clinical laboratories. No reputable source classifies as pathogenic/likely pathogenic.
Sources
clinvar ↗
BA1 The allele frequency in gnomAD v4.1 is 6.3e-7 (0.000063%), which is far below the 1% threshold required for BA1. This variant is effectively absent from population databases. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 AF=6.3e-7
  • well below 1% BA1 threshold.
Sources
gnomad_v4 ↗
BS1 The allele frequency in gnomAD v4.1 is 6.3e-7 (0.000063%), which is far below the 0.3% threshold required for BS1. This variant is effectively absent from population databases. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 AF=6.3e-7
  • well below 0.3% BS1 threshold.
Sources
gnomad_v4 ↗
BS2 Only one heterozygous carrier has been observed in gnomAD v4.1 (1/1,586,736 alleles, 0 homozygotes). BS2 requires observation in a homozygous state in healthy adults, or at a frequency too high for a fully penetrant dominant disorder. The single heterozygous observation does not meet this threshold. Details ▾Hide ▴
Evidence considered
  • Single heterozygous allele in gnomAD v4.1
  • no homozygotes observed.
Sources
gnomad_v4 ↗
BS3 No well-established functional studies demonstrating no damaging effect have been identified for this variant. BayesDel predicts a benign score (-0.237) and REVEL is low (0.296), but computational predictions alone are insufficient for BS3, which requires experimental functional data showing no deleterious effect in a validated assay system. Details ▾Hide ▴
Evidence considered
  • BayesDel -0.237 (benign prediction)
  • but no experimental functional data demonstrating no damaging effect.
Still missing
  • No experimental functional studies showing benign effect.
Sources
bayesdelrevel
BS4 No segregation data are available to evaluate lack of cosegregation with disease. BS4 requires observation that the variant does not segregate with disease in affected family members. Details ▾Hide ▴
Evidence considered
  • No family segregation data available.
Still missing
  • No family studies available for non-segregation assessment.
BP1 BP1 applies when a missense variant occurs in a gene where the primary disease mechanism is through truncating (loss-of-function) variants. TERT is associated with telomere biology disorders through both pathogenic missense and truncating germline variants. Pathogenic missense variants in TERT are well-established in the literature, including in the TEN and RT domains. Therefore, BP1 does not apply to TERT missense variants. Details ▾Hide ▴
Evidence considered
  • TERT disease mechanism includes both pathogenic missense and truncating variants
  • BP1 not applicable.
Sources
pvs1_gene_context
BP2 No evidence of this variant occurring in trans with a known pathogenic variant in TERT. BP2 requires observation in trans with a pathogenic variant in a recessive disorder, or in cis with a pathogenic variant in any inheritance pattern. Details ▾Hide ▴
Evidence considered
  • No data on trans/cis configuration with other TERT variants.
Still missing
  • No phasing data available.
BP5 BP5 applies when a variant is found in a case with an alternate molecular basis for disease. No such alternate molecular explanation has been documented for the case(s) with this variant. Insufficient clinical context is available to evaluate this criterion. Details ▾Hide ▴
Evidence considered
  • No alternate molecular basis for disease identified in available data.
Still missing
  • No case-level clinical or molecular data available.
BP6 This variant is reported in ClinVar as Uncertain significance (VUS) by two clinical laboratories (Labcorp/Invitae and Ambry Genetics). BP6 requires classification as benign or likely benign by a reputable source. No reputable source has classified this variant as benign or likely benign. Details ▾Hide ▴
Evidence considered
  • ClinVar: VUS from 2 clinical laboratories. No reputable source classifies as benign/likely benign.
Sources
clinvar ↗
PS5 No evidence of a different pathogenic missense variant at codon 292 of TERT with a different amino acid change. PS5 requires an established pathogenic variant at the same residue with a different amino acid substitution. Details ▾Hide ▴
Evidence considered
  • No pathogenic missense variants at p.Thr292 with different amino acid changes identified.
Not applicable · 3· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant (c.875C>T, p.Thr292Met) and does not fall into the null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants required for generic PVS1 application per ClinGen SVI PVS1 recommendations (PMC6185798). Details ▾Hide ▴
Evidence considered
  • Missense variant
  • not a null variant type eligible for PVS1 under generic ACMG/AMP framework.
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PM5 N/ANo same-residue comparator variants with different amino acid changes and confirmed pathogenicity were identified; automated PM5 candidate harvesting was unable to confirm classic PM5 semantics for this variant. Details ▾Hide ▴
Evidence considered
  • No same-residue pathogenic missense variants with different amino acid changes identified.
Sources
pm5_candidates
BP7 N/AThis is a missense variant (c.875C>T, p.Thr292Met), not a synonymous variant. BP7 applies only to synonymous (silent) variants for which splicing algorithms predict no impact on the splice consensus sequence or a new cryptic splice site. Details ▾Hide ▴
Evidence considered
  • Variant is missense
  • not synonymous
  • BP7 not applicable.

Identifiers

Gene
TERT
Transcript
NM_198253.2
Coding (HGVS c.)
NM_198253.2:c.875C>T
Protein (HGVS p.)
NP_937983.2:p.(Thr292Met)
GRCh38
chr5:1294011 G>A
GRCh37
chr5:1294126 G>A
ClinVar
1379490
COSMIC
COSV99716364

Gene diagram

Every interpreted variant in TERT, mapped onto the exon structure of NM_198253.2. Select a row to find it on the plot.

TERTNM_198253.2
Fetching transcript structure from UCSC…
gnomAD v4.1 1 / 1,586,736 alleles AF 6.3e-07 · 0 homozygotes
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 6.3e-07 · 1 / 1,586,736 alleles · 0 hom
South Asian1 / 87,600 1.1e-05
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American, European (non-Finnish).

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 6.30225e-07; MAF= 0.00006%, 1/1586736 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 1.14155e-05; MAF= 0.00114%, 1/87600 alleles, homozygotes = 0).

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat +44 bp
0.010
SpliceAI acceptor gainat -32 bp
0.000
SpliceAI donor lossat -96 bp
0.000
SpliceAI donor gainat +368 bp
0.000
Pangolin splice lossmagnitude shown
-0.010
Pangolin splice gain
0.010

Other predictors

REVEL
0.296
BayesDel
-0.237

How the predictions were used

BP4 SupportingMultiple lines of computational evidence suggest this variant is tolerated and does not impact gene product function. BayesDel predicts a benign score (-0.237), REVEL score is low (0.296, below the 0.5 threshold for deleterious prediction), and SpliceAI predicts no splicing impact (max delta = 0.01). The convergence of independent computational tools toward a benign prediction satisfies BP4 at supporting level. Details ▾Hide ▴
Evidence considered
  • BayesDel: -0.237 (benign prediction).
  • REVEL: 0.296 (below 0.5 threshold).
  • SpliceAI: max delta 0.01 (no predicted splice impact).
Sources
bayesdelrevelspliceai ↗
PP3 Multiple in silico tools do not support a damaging effect for this variant. REVEL score is 0.296 (below the commonly used 0.5 threshold for pathogenicity). BayesDel score is -0.237 (in the benign range). SpliceAI predicts no splicing impact (max delta = 0.01). These computational predictions do not meet the threshold for PP3, which requires multiple lines of computational evidence supporting a deleterious effect. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.296 (below 0.5 pathogenicity threshold).
  • BayesDel: -0.237 (benign prediction).
  • SpliceAI: max delta 0.01 (no splice impact).
Sources
revelbayesdelspliceai ↗
BP7 N/AThis is a missense variant (c.875C>T, p.Thr292Met), not a synonymous variant. BP7 applies only to synonymous (silent) variants for which splicing algorithms predict no impact on the splice consensus sequence or a new cryptic splice site. Details ▾Hide ▴
Evidence considered
  • Variant is missense
  • not synonymous
  • BP7 not applicable.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.296. BayesDel score = -0.237158.

3 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.

Recorded publications

  • Dyskeratosis Congenita and Related Telomere Biology Disorders.
    Adam MP et al. · 1993
    GeneReviews chapter on Dyskeratosis Congenita and Related Telomere Biology Disorders. Discusses TERT as one of several genes associated with telomere biology disorders, providing clinical and genetic overview at the gene level. NM_198253.2:c.875C>T was not identified in this publication.
    Does not name this variant
    PMID 20301779 ↗
  • Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional Version.
    PDQ Cancer Genetics Editorial Board · 2002
    PDQ cancer genetics summary on Cancer Genetics Risk Assessment and Counseling. Reviews hereditary cancer syndromes and genetic testing approaches. NM_198253.2:c.875C>T was not identified in this publication.
    Does not name this variant
    PMID 26389258 ↗
  • Genetics of Skin Cancer (PDQ®): Health Professional Version.
    PDQ Cancer Genetics Editorial Board · 2002
    PDQ cancer genetics summary on Genetics of Skin Cancer. Provides overview of hereditary melanoma syndromes and associated genes including TERT promoter mutations. NM_198253.2:c.875C>T was not identified in this publication.
    Does not name this variant
    PMID 26389333 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 1 / 1,586,736 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.010 Open source ↗
ClinVar 2 Uncertain significance Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
OncoKB Captured OncoKB source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 6.30225e-07; MAF= 0.00006%, 1/1586736 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 1.14155e-05; MAF= 0.00114%, 1/87600 alleles, homozygotes = 0).

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories). (ClinVarID = 1379490)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.296. BayesDel score = -0.237158.

Functional

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. TERT is an enzyme that functions to maintain telomere length and genomic stability. The TERT promoter is frequently mutated in various cancer types.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV99716364, n = 2 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.